Retinoids are attracting interest as potential chemopreventive and chemotherapeutic agents for a variety of human cancers. Although the molecular responses elicited by retinoids are poorly understood, these responses appear to cause cellular differentiation. The differentiating effects of retinoids fit a parallel model for tumor development that may account for their success in the clinic. This model suggests that certain tumors arise due to improper differentiation of specific precursor cells. Tumors of the colon represent one type of neoplastic disease that fits this.lack of differentiation. model. Development of normal colon epithelial cells proceeds through a systematic differentiation of cells that emerge from stem cells within the base of colon crypts. Genetic mutations in the adenomatous polyposis coli (APC) gene are thought to create stem cells that fail to differentiate and, therefore, produce colon polyps and colon tumors. Using microarray expression profiling, we have found molecular evidence supporting lack of differentiation as the mechanism for development of colon polyps and tumors. Our preliminary data revealed a surprising prevalence of down-regulated genes in sporadic colon polyp and colon tumor colonocytes as compared to normal colonocytes. Among the genes absent were a number of retinoic acid response genes. The absence of these response genes was paralleled by the lack of expression of retinol dehydrogenase 5 and a novel, colon specific retinol dehydrogenase termed RDHL. The RDHL promoter is induced by APC and the colon specific transciption factor Cdx2. Based on these observations, we hypothesize that APC and Cdx2 control colonocyte differentiation, in part, by regulating retinoid responsiveness within the colon crypt. Mutations in APC or Cdx2 lead to a failure to produce retinoic acid by colon epithelial cells. This failure to synthesize retinoic acid impairs colonocyte differentiation and contributes to colon polyp and colon tumor development. In this proposal, we will examine the specific hypothesis that APC and cdx2 control retinoid biosynthesis and responsiveness.